PROJECT SUMMARY/ABSTRACT Approximately 32-35 million adults in the US population (16%) experience an episode of major depression in their lifetime, and commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Given that antidepressants such as SSRIs are also commonly used to treat other psychiatric disorders, such as generalized anxiety disorder and obsessive-compulsive disorder, it is of critical importance to determine the differences between remitters and non-remitters to antidepressant treatment. Our overall research program addresses this question by assessing antidepressant treatment resistance in mice. Preliminary data indicate that both molecular and neural-circuit based approaches to modifying the dentate gyrus may be able to convert behavioral non-responders to fluoxetine (a SSRI) into responders. Further preliminary data indicate that these approaches may also work as augmentation strategies for several other classes of antidepressants. The Specific Aims are: 1) Test the hypothesis that Activin signaling based modifications of dentate gyrus can alter the behavioral response to fluoxetine through modulation of young adult-born granule cells; 2) To test the hypothesis that circuit-based approaches to silencing mature dentate gyrus granule cells can alter the behavioral response to fluoxetine and to determine whether there are functional differences in DG inputs between responders and non-responders; and 3) Test the hypothesis that alterations in DG granule cells are a common feature of behavioral non-response to different antidepressant treatments.